The mesolimbic dopamine system, which originates in the ventral tegmental area and projects to the nucleus accumbens (NAc), is involved in the pleasurable (hedonic) and rewarding effects of a variety of substrates, including drugs of abuse, food, and sexual behavior. Drugs of abuse cause complex neuroadaptations in this system, some of which are associated with altered drug sensitivity. One neuroadaptation involves cAMP response element-binding protein (CREB), a transcription factor that is activated in striatal regions by psychostimulants. CREB in the NAc appears to regulate the rewarding and aversive effects of cocaine. Stimulation of cAMP-dependent protein kinase A (PKA), which activates CREB, in the NAc decreases cocaine reward. Similarly, elevation of CREB expression in the NAc decreases cocaine reward and makes low doses of the drug aversive. Conversely, blockade of PKA activity or overexpression of a dominant-negative CREB, which functions as a CREB antagonist, in the NAc increase cocaine reward. These findings suggest that CREB activation in the NAc counteracts drug reward and increases drug aversion.
Cocaine alters neuronal excitability and neurotransmitter levels in the brain, particularly the mesolimbic dopamine system. Cocaine withdrawal is accompanied by signs of depression and other mood disorders in humans. The biological basis of mood disorders like depression is not understood, but may be caused by genetic and environmental factors. Physically and emotionally stressful events can also influence the etiology of depression, possibly causing subtle brain changes and alterations in gene expression. Thus, depression may have an important acquired component, caused by neuroadaptations in response to environment and experience.
The therapeutic actions of antidepressants appear to involve neuroadaptations. Most antidepressant treatments (including tricyclic and atypical antidepressants, selective serotonin reuptake inhibitors, electroconvulsive therapy) have common actions on components of the cAMP pathway. Common actions include activation of PKA and the transcription factor CREB in the hippocampus, a brain region associated with emotion. CREB plays a critical role in the expression of numerous genes. Understanding causal relations among CREB function, gene expression, and the therapeutic effects of antidepressants might provide explanations for why antidepressants require sustained treatment for effectiveness. Additionally, because some genes regulated by CREB may be therapeutic while others may be pathophysiological, a more general understanding of the role CREB in behavior might help to elucidate the biological basis of depressive syndromes.
Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CREB in the hippocampus. In this region, it is believed that increasing CREB activity is beneficial, because CREB controls some growth factors (e.g., BDNF) in the brain. However, there is no evidence that increasing CREB in the hippocampus is associated with the therapeutic effects of antidepressants.
Although much research on the molecular mechanisms of depression and antidepressant actions has focused on the hippocampus, the NAc may also have relevance. This basal forebrain region is innervated by dopamine neurons of the ventral tegmental area, as well as by noradrenergic and serotonergic inputs. The NAc contributes importantly to the pleasurable effects of food, sexual behavior, novelty, and addictive drugs.
Most current antidepressants act primarily on brain levels of noradrenaline or serotonin. There is some evidence that dopamine systems might be involved in depressive syndromes. Blocking dopamine receptors in the brain causes anhedonia (a decreased ability to experience pleasure), a defining feature of depression. Nomifensine, a dopamine reuptake inhibitor, was a clinically effective antidepressant, further implicating dopaminergic dysfunction in depression. Nomifensine was taken off the market because it caused lethal allergic reactions in some people.
The present invention provides methods for treating depression and other psychiatric diseases associated with symptoms of depression. The invention is based, in part, on discovery that stressors that cause symptoms of depression in rats increase the activation of CREB in the nucleus accumbens. CREB activation results in the activation of the prodynorphin gene, which encodes the opioid peptide dynorphin. Dynorphin is an agonist of the kappa opioid receptors in the brain, and enhances symptoms of depression. The kappa receptor antagonists norBNI and GNTI demonstrate antidepressant effect in rats, which is mediated by a disinhibition of dopamine release in the nucleus accumbens.
The invention features, in one aspect, a method for treating a depressive disorder, or reducing cAMP response element-binding protein (CREB) activation in a mammal, e.g., a human patient, by administering an effective amount of a kappa receptor antagonist. Kappa receptor antagonists are particularly useful for treating major depression, dysthymia, bipolar disorder (manic depression), and post traumatic stress disorder; however, any psychologic or psychiatric disorder having symptoms that include depression are amenable to treatment according to the present methods. The kappa receptor antagonists can bind either reversibly or irreversibly.
The kappa receptor antagonists can be administered systemically, including, for example, by intravenous, intramuscular, or subcutaneous injection, orally, or by topical or transdermal application, provided that the kappa receptor antagonist is capable of penetrating the blood-brain barrier sufficiently to be effective. Alternatively, the kappa receptor antagonists can be centrally administered using, for example, by an intrathecal, intracerebroventricular, or intraparenchemal injection. Useful kappa receptor antagonists include, for example, nor-binaltorphimine (norBNI), GNTI (5xe2x80x2-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5xcex1-epoxy-3,14-dihydroxy-6,7-2xe2x80x2,3xe2x80x2-indolomorphinan), and DIPPA (2-(3,4-dichorophenyl)-N-methyl-N-[(IS)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide).
By xe2x80x9cdepressive disorderxe2x80x9d is meant any psychologic or psychiatric disorder which is associated with symptoms of depression. Treatable depressive disorders can be characterized by an inhibition or reduction of dopaminergic function in the nucleus accumbens, e.g., major depression, dysthymia, bipolar disorder (manic depression), and post-traumatic stress disorder.
By xe2x80x9ckappa antagonistxe2x80x9d is meant any chemical compound which has affinity for the kappa opioid receptor and attenuates or prevents the binding or physiologic response associated with dynorphin binding. Kappa antagonists which are useful according to this invention can be competitive or non-competitive inhibitors of dynorphin binding. Inverse agonists, compounds which cause the opposite effect of the agonist, can be used in place of the kappa antagonists in any of the methods of this invention. Preferably, kappa antagonists (or inverse agonists) bind with a dissociation constant of less than 10xe2x88x927,10xe2x88x928,10xe2x88x929,10xe2x88x9210,10xe2x88x9211,10xe2x88x9212, or even 10xe2x88x9215 moles/L.